Role Of Gut Microbiota Of NLRP3-deficient Mice In Depressive-like Behaviour

Objective:Major depressive disorder(MDD),characterized by emotional dysfunction,is one of the most prevalent psychiatric disorders worldwide.Increasing evidence suggests that the dysbiosis of gut microbiota composition may be an important factor leading to depression.According to the inflammasome hypothesis of depression,neuroinflammatory pathways play a role in MDD.Inflammasomes have been found to interact with the gut microbiota,which is associated with depression,but the detailed mechanisms underlying the interaction are not well understood.This study investigated the gut microbiota from NLRP3-deficient mice,and clarified that NLRP3 KO mice showed decreased depressive-like behaviors,which were eliminated upon cohousing or after fecal transfer.The results of this study provide translational evidence that the gut microbiota from NLRP3 KO mice may serve as a novel therapeutic target for depression Methods: Sucrose preference test(SPT),forced swimming test(FST),Tail suspension test(TST),open field test(OFT)was performed to demonstrate the differences between NLRP3 KO and WT.Co-culture of NLRP3 KO with wild-type mice was used to verify the effects of intestinal flora on their behavior.The gut microbiota of NLRP3 KO mice improving depression behavior was detected by the fecal microbiota transplantation(FMT).The changes in gut microbiota was detected by 16 S DNA.The role of circHIPK2/ gut microbiota axis in astrocyte activation was illustrated by Western blot and immunostaining after lentivirus vector transfection in vivo.Results: 1)NLRP3 KO gut microbiota affected depressive-like behavior;2)NLRP3 inflammasome deficiency affected the gut microbiota composition;3)Transplantation of the NLRP3 KO gut microbiota ameliorated CUS-induced depressive-like behaviors;4)Transplantation of the NLRP3 KO mouse gut microbiota alleviated astrocyte loss in CUS mice;5)Transplantation of the NLRP3 KO gut microbiota inhibited the increased expression of circHIPK2 in CUS mice;6)Knockdown of circHIPK2 expression reversed astrocyte loss induced by CUS;7)Knockdown of circHIPK2 expression in astrocytes inhibited depressive-like behavior induced by CUS.Conclusions: NLRP3 KO mice exhibited less depressive-like behavior and that their gut microbiota composition is significantly altered.NLRP3 KO mice gut microbiota transplantation significantly ameliorated the depressive-like behavior induced by CUS.The mechanism underlying this process was the regulation of astrocyte dysfunction via circHIPK2.